Project Summary In this grant, we propose to define functions of a subset of lncRNAs that are modulated by interferon, toll-like receptors and influenza infection. We utilized transcriptome sequencing of pDCs treated with type I interferon and TLR7 agonist R848, and R848 together with IFN-I blockade to identify 48 lncRNAs that are differentially regulated upon immune stimulation and during influenza infections. Based on pathway analysis, we hypothesize that these lncRNAs could interact with signaling molecules, transcription factors or antiviral genes to modulate antiviral function during influenza infection. However, very few lncRNAs have been investigated in the context of influenza infection. Using nickase deficient Cas9 system, we will induce the expression of these lncRNA during viral infection and screen for innate immune, antiviral responses as well as their effect on viral entry or egress pathways. To identify the functions for this subset of lncRNAs, we will utilize an MS2-MBP pull downs and mass spec to identify protein binding partners to these lncRNAs. This proposal has the potential to identify functions of lncRNAs that could orchestrate antiviral immunity during influenza infection.